Transient inactivation of the posterior paraventricular nucleus of the thalamus blocks cocaine-seeking behavior

doi:10.1016/j.neulet.2015.10.016

Neuroscience Letters

Volume 608, 3 November 2015, Pages 34-39

https://doi.org/10.1016/j.neulet.2015.10.016 Get rights and content

Highlights

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The paraventricular nucleus of the thalamus (PVT) has recently gained attention because of its involvement in the modulation of drug-directed behavior.
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Cue-induced reinstatement of cocaine seeking is more sensitive to temporary inactivation of the pPVT than cue-induced reinstatement of natural reward seeking.
•
The pPVT plays an important role in neuronal mechanisms that drive cocaine-seeking behavior.

Abstract

Originally studied for its role in energy homeostasis, the paraventricular nucleus of the thalamus (PVT) has recently gained attention because of its involvement in the modulation of drug-directed behavior. The posterior part of the PVT (pPVT) is connected with brain structures that modulate motivated behavior, and we tested whether the pPVT plays a pivotal role in cocaine seeking. The aim of the present study was to investigate whether transient inactivation of the pPVT prevents cue-induced reinstatement of cocaine seeking but not natural reward seeking. Male Wistar rats were trained to associate a discriminative stimulus (S⁺) with the availability of cocaine or a highly palatable conventional reinforcer, sweetened condensed milk (SCM). Following extinction, the cocaine S⁺ and SCM S⁺ elicited comparable levels of reinstatement. Intra-pPVT administration of the γ-aminobutyric acid-A (GABA_A) and GABA_B receptor agonists muscimol and baclofen (0.06 and 0.6 mM, respectively) prior to the presentation of the cocaine or SCM S⁺ completely prevented the reinstatement of cocaine seeking, with no statistically significant effects on SCM seeking. These data show that the pPVT plays an important role in neuronal mechanisms that drive cocaine-seeking behavior.

Introduction

The high relapse rate and long-lasting vulnerability to relapse in abstinent individuals are among the challenges encountered in the effective treatment of drug addiction [17], [25], [27], [28]. One hypothesis that can explain the long-lasting nature of drug-seeking behavior is that the neuronal circuits that mediate the control of drug-seeking and drug-taking behaviors have common motivational neuronal substrates that are not specific to addiction-related processes but are robustly activated by drugs.

The thalamus was recently proposed to be included in the neurocircuitry of addiction [15], [24]. The paraventricular nucleus of the thalamus (PVT), considered a communication point between the ventral and dorsal striatum and lateral hypothalamus, has drawn attention because it plays a key role in energy homeostasis, arousal, endocrine regulation, and reward [3], [14], [30], [35] and has been reported to be engaged in the effects of drugs (e.g., cocaine and ethanol). The posterior part of the PVT (pPVT) projects to the nucleus accumbens (NAC), extended amygdala, and medial prefrontal cortex (mPFC) [18], placing the pPVT at a pivotal point to modulate motivated behavior.

Earlier findings showed that the PVT is activated by the presentation of cocaine-paired cues [5]. Recent findings demonstrated that transient inactivation of the PVT prevented cocaine prime-induced reinstatement [12] and the expression of conditioned place preference [6]. Moreover, data from this laboratory demonstrated a positive correlation between cocaine-seeking behavior that was induced by cocaine-related stimuli and PVT activation (measured by Fos-expressing neurons), whereas presentation of the stimulus that was predictive of a potent food reward (SCM S⁺) elicited reinstatement but induced only nonspecific Fos expression that was not correlated with behavior, confirming that the PVT, as a whole, is recruited during the conditioned reinstatement of cocaine seeking [22].

Based on the previous observations that the PVT is differentially recruited by stimuli that are conditioned to the availability of cocaine vs. palatable food reward and that the pPVT is specifically connected to brain structures that are involved in the regulation of motivated behavior, the aim of the present study was to evaluate the importance of pPVT integrity in cocaine-seeking behavior vs. behavior that is motivated by stimuli that are conditioned to a highly palatable conventional reinforcer (sweetened condensed milk [SCM]). This was achieved by transiently inactivating the pPVT using the γ-aminobutyric acid-A (GABA_A) and GABA_B receptor agonists muscimol and baclofen, respectively, administered together before conditioned reinstatement.

Section snippets

Animals

Forty-two male Wistar rats (Charles River, Wilmington, MA, USA), weighing 200–225 g upon arrival, were housed two per cage in a temperature- and humidity-controlled vivarium on a reverse 12 h/12 h light/dark cycle with ad libitum access to food and water. All of the procedures were conducted in strict adherence to the National Institutes of Health Guide for the Care and Use of Laboratory Animals and were approved by the Institutional Animal Care and Use Committee of The Scripps Research Institute.

Drugs

Results

Two rats in the SCM group and four rats in the COC group were lost because of cannula misplacement (n = 2 for SCM and 1 for COC), health complications (n = 2 for COC), or the lack of acquisition of COC self-administration (n = 1), thus reducing the number of animals to n = 17 for COC and n = 19 for SCM.

Discussion

Although reward-predictive environmental stimuli (S⁺) produced strong and identical recovery of responding, regardless of whether they were conditioned to a conventional reward (SCM) or drug reward (cocaine), transient inactivation of the pPVT completely inhibited cocaine-seeking behavior but had no significant effect on the motivational actions of stimuli that were conditioned to SCM. These findings implicate the pPVT as an important site that regulates the control of cocaine seeking by

Acknowledgements

This is publication number 28067-MCN from The Scripps Research Institute. Research support: NIH/NIDA DA033344 (R.M.F), DA08467, and DA07348 (F.W.). We thank M. Bainier for technical assistance and M. Arends for assistance with preparation of the manuscript.

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Research paperTransient inactivation of the posterior paraventricular nucleus of the thalamus blocks cocaine-seeking behavior

Highlights

Abstract

Introduction

Section snippets

Animals

Drugs

Results

Discussion

Acknowledgements

Neurosci.

Brain Res.

Drug Alcohol Depend.

Brain Res.

Neuroscience

Neurosci. Biobehav. Rev.

Lancet

J. Neurosci. Methods

Brain Res.

Brain Res. Brain Res. Rev.

Pharmacol. Biochem. Behav.

Preferential effects of the metabotropic glutamate 2/3 receptor agonist LY379268 on conditioned reinstatement versus primary reinforcement: comparison between cocaine and a potent conventional reinforcer

J. Neurosci.

Anterior thalamic paraventricular nucleus is involved in intermittent access ethanol drinking: role of orexin receptor 2

Addict. Biol.

Evidence for conditional neuronal activation following exposure to a cocaine-paired environment: role of forebrain limbic structures

J. Neurosci.

Glutamate transmission in the nucleus accumbens mediates relapse in cocaine addiction

J. Neurosci.

Paraventricular thalamus mediates context-induced reinstatement (renewal) of extinguished reward seeking

Eur. J. Neurosci.

Progressive ratio as a measure of reward strength

Science

Cocaine- and amphetamine-regulated transcript (CART) signaling within the paraventricular thalamus modulates cocaine-seeking behaviour

PLoS One

Research paper
Transient inactivation of the posterior paraventricular nucleus of the thalamus blocks cocaine-seeking behavior